Work

The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation

Year: 2025

Type: article

Abstract: The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the i-space. The i-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract i-space, revealing its scale-free architecture-elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive i-space sampling beyond site-centric models, supporting the "oxiform conjecture". This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms.

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103523

Authors: James N. Cobley, Panagiotis N. Chatzinikolaou, Cameron A. Schmidt

Institutions: University of Dundee, Aristotle University of Thessaloniki

Language: English

Topic: Redox biology and oxidative stress

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $4,310

Funders: University of Dundee, Medical Research Council